DiscoveryBioMed, Inc. (DBM) achieved Phase 1 SBIR milestones and seeks to continue a mature program that has progressed to the hit-to-lead drug validation, prioritization and progression stage. DBMs major over-arching goal for this program is to identify novel clinical candidate CFTR Corrector Ligands (CFCLs) for the treatment of CF through the completion of a focused Drug Discovery program and accompanying Critical Progression Path, which utilize disease-relevant human cell systems. These compounds have the potential to be disease-modifying with dramatic effects on disease progression as well as CF patients well-being and quality of life. DBM, academic collaborators, and industry consultants (with >70 years experience in Drug Discovery) have refined secondary validation and tertiary prioritization assays and their order in a Critical Path such that the small molecules that are most potent and druggable are systematically identified and progressed forward towards selection of the best compound(s) for progression to Preclinical Development. Phase 2 aims will focus on identifying and progressing the best lead CFCLs from different chemical scaffolds. This CF Drug Discovery program is part of a larger initiative on CF and other chronic respiratory diseases that represent DBMs most mature drug discovery umbrella to date (see Commercialization Plan). For this revised Phase 2 SBIR-driven program application, DBM proposes three key milestones, which follow a Drug Discovery Critical Path of validation, optimization and, ultimately, the selection of inhaled clinical candidate compounds primarily (with an eye on secondary examination of the oral route of administration): Milestone 1 - Hit to Lead Validation, which will profile emerging hit-to-lead CF corrector ligands in comparison to a potent benchmark lead compound identified in Phase 1, DBM 99H7. Milestone 2 - Structure-Activity Relationship (SAR) Development and Lead Optimization, which will profile further and optimize the lead CF corrector compounds. Milestone 3 - Further Profiling of Lead Compounds and Selection of Clinical Candidate(s), which will identify the best compounds for Preclinical Development and Clinical Trials. Specific aims, listed under each key milestone, script key experimental tasks within the Drug Discovery Critical Path; these are defined in more detail elsewhere in Goals and Milestones and Research Strategy sections. They represent key parameters and features of compounds that will assist with the identification of the best CFCLs. Mechanistically, the most desired drug is one that both corrects the folding defect in delF508-CFTR within the endoplasmic reticulum as well as activates or opens the delF508-CFTR Cl- channel in the secretory pathway and at the apical plasma membrane. Added benefits may include the correction of other dysregulated epithelial cell functions, such as inhibition of hyperactive epithelial sodium channels (the ENaCs) as well as the opening or up- regulation of other Cl- channels that might amplify mutant CFTR function in the apical cell membrane. DBM believes that its benchmark lead CFCL drug, DBM 99H7, is an example of a delF508-CFTR corrector, a delF508- CFTR opener, and an ENaC inhibitor. Through the study of initial lead and lead classes of CFCLs found in this CF human airway cell-driven drug discovery program during Phase1 of the SBIR grant, we have learned much about the features of lead drugs that are most desired and how to best profile and progress them. DBM is confident that this Phase 2 program will yield a primary CFCL clinical candidate as well as back-up lead CFCLs to progress forward into a therapeutic development spinout company and, ultimately, to out-license with a BioPharma. DBM, Inc.